Development of microfluidic systems for therapeutic applications

Abstract

The development of a microfluidic-based strategy is presented for investigating the functional behaviour of hydrogel spherical beads which are employed in the clinic as embolic agents and drug delivery systems for the treatment of hypervascularised tumours and arteriovenous malformations. For this purpose, biomimetic microchannel networks were designed and fabricated by micromilling technology. Microdevices architecture reproduced characteristic features of microcirculatory arteriolar systems. The miniaturisation allowed for coupling with microscope-based technology and in situ visualisation of particles/cells behaviour.

The flow dynamics of red blood cells (RBCs) suspensions within the aforementioned biomimetic microfluidic devices was investigated, by using in-house developed micro-Particle Image Velocimetry (?-PIV) methods and image analysis techniques to quantify fluid velocity fields, cell-free layer width and RBCs spatial distribution. Results demonstrated the potential of the developed microfluidic devices for reliably reproducing peculiar properties of RBCs flow behaviour within human microcirculatory systems, including the relationship between cell-depletion layer width and microvessel diameter, and the dependence of RBCs distribution on the local Reynolds number. These findings opened the way for the application of the developed microfluidic devices as a biomimetic platform for investigating the performance of embolic beads.

The flow behaviour of hydrogel beads within biomimetic microfluidic environments was investigated by adopting a two-steps approach, in which beads hydrodynamics was firstly studied within straight microchannels (Step I) and subsequently within network-like microchannel constructs (Step II). For this purpose, microscopy-based analysis techniques were developed in order to quantify bead radial position and axial velocity. Results demonstrated that bead flow behaviour depended on a complex interplay between the governing physical parameters, which included fluid rheology, fluid inertia (i.e., Reynolds number) and particle relative dimension (i.e., degree of confinement). Notably, it has been demonstrated that for a given combination of such parameters beads underwent oscillatory dynamics which have been thoroughly characterised experimentally. Further, beads partitioning at bifurcations, penetration efficacy and spatial location of the embolic events within biomimetic microchannel networks were investigated. The experimental observations presented here can provide relevant insight into the mechanisms governing the spatial distribution of embolic beads within tumour vascular systems. Finally, the spatiotemporal dynamics of drug elution from hydrogel embolic beads was investigated within the aforementioned biomimetic microchannel networks. Both on-chip analysis and off-chip analysis techniques were developed for quantifying the kinetics of drug elution and the amount of eluted drug from single embolic beads. Results revealed that drug elution from hydrogel embolic beads depended on the local hydrodynamics at the embolic site and on the location of the embolic event within the vascular network (i.e., proximal or distal embolisation). A numerical model was developed in order to better understand the role played by flow dynamics environment on the spatial distribution of the eluted drug at biomimetic bifurcations.

In conclusion, the results of this study have established that microfluidics could be potentially employed as an alternative to animal models for investigating the performance and functional behaviour of hydrogel beads used in cancer therapy and targeted drug delivery.

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Identifiers

ORCID for Xunli Zhang: orcid.org/0000-0002-4375-1571

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